There is now convincing evidence that early cancer detection can lead to better patient outcomes through early administration of therapy. One of the best ways to early diagnose cancer is to use serum biomarkers. Unfortunately, for most cancers, we do not have effective biomarkers for either early detection or prediction of therapeutic response. With this grant application, we aim to identify such biomarkers for ovarian cancer - the most lethal gynecological malignancy in the United States. The major objective of this grant application is to examine if a panel of newly discovered ovarian cancer biomarkers (via an integrated systems biology proteomic approach), in combination with the classical ovarian cancer biomarker, CA125 and 9 other promising biomarkers such as HE4 and a group of kallikrein enzymes, constitutes a new, multiparametric serum panel for early ovarian cancer diagnosis with high sensitivity and specificity. By employing immunoassays and immuno-mass spectrometry-based technologies, we will perform a Phase I preclinical study on our top 40 novel biomarkers from which we will select only those displaying 98% specificity and 30% sensitivity for Phase II evaluation. The Phase ll case-control study, using validated immunoassays developed as part of this grant application, will utilize the PRoBE study design for sample collection and only those markers displaying at least 98% specificity and at least 70% sensitivity will proceed for an independent, blinded study using the EDRN CVC ovarian cancer reference sample set. It is anticipated that 2-4 new candidates, along with some of the 10 known markers will constitute a multiparametric panel with high specificity and sensitivity, suitable for early diagnosis and possible screening for ovarian cancer.